Oral controlled-release formulations provide maximum patient compliance and reduce the frequency of dosing to attain effective therapy. The intention of controlled-release formulations is to provide an extended duration of the pharmacological response after administration of the dosage form, than is ordinarily experienced after the administration of an immediate-release dosage form. The purpose of these formulations is to provide a constant concentration of the active substance in body fluids for a certain time period. However, the demand on controlled-release dosage forms is immense, the maximal therapeutic effect is to be reached using a minimum amount of active substance with reduced frequency of dosing and lesser degree of side effects, as well as minimized inter and intra individual effect variations. The dosage form could be single unit or multiple unit dosage form.
Single unit controlled-release dosage forms either pass undisintegrated through the gastrointestinal tract or release the entire drug in a burst (dose dumping). Such dosage forms are dependent upon gastric emptying rates and transit times and are also associated with a lot of intra and inter-individual variations.
Multiple unit dosage forms comprise a multiplicity of individual units contained within a rapid dissolving capsule, or compressed into a tablet, and soon after ingestion upon its dissolution are available as individual units in the G.I.T.
Several advantages with multiple unit dosage forms comprising a large number of small units have been described in the literature. It is, for example, possible to obtain a reproducible emptying of the units from the stomach into the small intestine when the particles are less than 1 to 2 mm. Dispersion over a large area in the gastrointestinal tract can give a more reproducible time for the passage, which is of advantage for the absorption process. In addition, a multiple unit preparation is preferable to one single drug unit as the dose is spread out in the intestine. The risk of local irritation and accumulation of several doses due to constriction in the alimentary canal are also considered to be lower.
U.S. Pat. Nos. 4,927,640 and 5,246,714 describe controlled-release insoluble beads coated with a membrane controlling drug release. Examples of insoluble inert material used are silicon dioxide, glass, or plastic resin particles. The core material has a standardized size and shape, preferably, spherical with an even surface with size of 0.15 to 0.25 mm. The preparation has several advantages, e.g., the particles contain a high percentage of the active ingredient and are not contaminated by soluble inert compounds, which is the case when cores of, e.g., lactose or sugar are covered by a therapeutically active compound. By using small dense particles of, e.g., silicon dioxide as the core material, it is possible to obtain highly concentrated beads (granules) of the active compound which is an advantage for high dosage preparations, e.g., magnesium chloride.
Dosage forms containing multiple layers have several advantages over the prior discussed arts. For example, U.S. Pat. No. 5,783,215 describes the multiple unit dose preparation capable of withstanding the mechanical stress, i.e., during compaction. This has been done by using inert and non-soluble cores of glass or sand particles or soluble cores such as sugar spheres capable of withstanding mechanical stress, in combination with a plasticizing layer. The active substance is dispersed in a solution of the hydrophilic polymer and applied to the core, which is again covered with controlled-release membrane. These beads have excellent mechanical and release characteristics.
WO 2004/105735 by Ranbaxy refers to a controlled-release composition containing units, wherein each unit includes a core, a first layer, and a second layer. In this application it has been disclosed that that inert core (soluble or swellable or insoluble) is first layered with active and one or more hydrophilic polymers. Further, it is layered with second layer of one or more polymers that are effective for controlled-release of active.
U.S. Pat. No. 5,229,135 discloses a sustained-release diltiazem pellet formulation having:                a. a central inactive sphere;        b. a plurality of alternating first and second layers surrounding the sphere to form a core, the first layer comprising a water soluble pharmaceutically acceptable polymeric material and the second layer comprising diltiazem or a pharmaceutically acceptable salt thereof; and        c. an outer coating comprising first inner membrane layers applied to said core, said first inner membrane layers comprising a first water-insoluble pharmaceutically acceptable polymer, and a single outer membrane forming a relatively thick and homogeneous layer surrounding said first inner membrane layers and comprising a second water-insoluble pharmaceutically acceptable polymeric material different from said first water-insoluble pharmaceutically acceptable polymer.        
Applying a polymer layer over the inert core before the active layer has some advantages. For example, the amount of time that the solution within the bead would be saturated with respect to drug may be maximized. Thus, by preventing the soluble core from being a reservoir for drug dissolution, the relative time that a saturated solution would remain within the bead during the release period can be increased considerably. This means that a substantially longer zero order drug-release phase (the phase when the drug release rate is essentially constant) will be obtained (and less in the undesirable declining release rate phase). By varying the thickness of the first polymeric layer, drug release profile can be altered in a predictable fashion, in particular for drugs with a moderate to high water-solubility.
A similar kind of dosage form is disclosed in U.S. Pat. No. 6,911,217. It describes a bead comprising (a) a core unit of a substantially water-soluble or water-swellable inert material, (b) a first layer on the core unit of a substantially water-insoluble polymer, (c) a second layer covering the first layer and containing an active ingredient, and (d) a third layer of polymer on the second layer effective for controlled-release of the active ingredient. The first layer of water-insoluble polymer is meant to control water penetration into the core.
U.S. Pat. No. 6,911,217 employs aqueous dispersion of water-insoluble polymers in its first and third layers. Use of polymers based on aqueous dispersion may lead to coalescence. Upon spraying the aqueous polymeric dispersion, the polymer particles are deposited on the surfaces of the pellets as colloidal particles. The colloidal particles come into direct contact with each other and form close-packed arrays due to water evaporation and increase the interfacial tension between water and polymer. Capillary forces then drive the particles to coalesce together. This coalescence may lead to enhance unwanted drug release variability, which should be avoided. Further, the aqueous based system requires high heat of vaporization that might require lengthy processing times leading to economic disadvantages. In addition to this, multiple units coated with aqueous based polymeric system can easily agglomerate in the coating process due to low inertia and momentum.
Therefore, it would be desirable to have a controlled-release composition in the form of multilayered multiple units that will deliver a constant and controlled-release of water-soluble drugs. Further, it is desired to have an advantageous process that would be less time consuming and economical.